Congenital heart disease is a multifactorial inheritance disorder that is induced by genetic and environmental factors during morphogenesis of the cardiovascular system in the embryos. Cardiac embryology plays an important role in reaching a definitive diagnosis, understanding the pathophysiology of disease, selecting the most appropriate medical/surgical treatment, and predicting complications and prognosis. Therefore, a thorough understanding of the processes involved in cardiac embryology is essential for pediatric cardiologists and cardiac surgeons. In this review, cardiac embryology and cardiovascular morphogenesis are discussed to assist physicians in understanding the etiological mechanisms of congenital heart disease. The molecular and cellular mechanisms of congenital heart disease using genetically engineered mice are available in any expertized textbooks and journals. Thus, in this review, basic and comprehensive outlines of cardiac embryology and morphogenesis are presented using illustrations.

Congenital heart diseases (CHD) result from abnormal development of the cardiovascular system and usually involve defects in specific steps or structural components of the developing heart and vessels. The determination of left-right patterning of our body proceeds as following steps: 1) A number of motile cilia in the node rotate and lead to the unidirectional leftward flow of extra-embryonic fluid in the node cavity, 2) This “Nodal Flow” induces asymmetric expression of Nodal, a member of TGF-β superfamily, only on the left side of the embryo that eventually activates the molecular pathway regulating the left-side specific morphogenesis. Disruption of any of these steps may result in left-right patterning defects or heterotaxy syndrome in human. Discovery of numerous factors involving the components of monocilia in the node and left side specific molecular pathway has provided new insights into not only heterotaxy syndrome but also associated CHD.

Chromosomal aneuploidy was the first recognized genetic cause of congenital heart disease (CHD). Methodologies to identify subchromosomal changes in the genome structure led to the discovery of chromosomal micro deletion or copy number variants (CNVs). Chromosomal micro deletion syndrome, including the 22q11.2 deletion syndrome and Williams syndrome, can be identified using fluorescence in situ hybridization (FISH). CNVs are deletions of over 1 kb or amplifications of DNA segments that principally result from inappropriate recombinations. These are detected by cytogenetic analyses, often in combination with FISH and/or array-comparative genomic hybridization. Since 1990’s, CHD-causing gene mutations have been discovered in the TBX5 and NKX2.5 genes by linkage analyses in familial cases and by sequencing analyses of candidate genes. Currently, next-generation sequencing allows reading of the exome and even the whole genome. This approach identifies a large number of variants; however, discriminating pathogenic variants from the non-pathogenic ones is essential to its success. Next-generation sequencing is expected to identify additional CHD-causing genes, which will further clarify the molecular mechanisms involved in cardiac development.

Cardiomyopathies are defined as abnormalities of the ventricular myocardium. Pediatric cardiomyopathies are rare diseases. Increasingly, the importance of genetic mutations in the pathogenesis of isolated or syndromic pediatric cardiomyopathies is becoming apparent. Pediatric cardiomyopathies are genetically heterogeneous with many different causative genes and multiple mutations in each gene. Variants in the same gene can cause different phenotypes, and variants in different genes can cause the same cardiomyopathy phenotype. There are multiple modes of inheritance for cardiomyopathies, including autosomal dominant, autosomal recessive, X-linked, and mitochondrial. Published guidelines have recommended approaches for genetic testing and family screening in patients with isolated, autosomal-dominant cardiomyopathy. The increasing application of genomic analysis to the pediatric cardiomyopathy population is creating a wealth of information that requires expanded registry participation to further understanding of the pathogenic mechanisms underlying pediatric cardiomyopathies and the genetic, environmental, and other, as of yet undiscovered, modifying factors that impact the severity of disease. This compendium summarizes current knowledge of the genetic and molecular origins of the most common phenotypic presentations of pediatric cardiomyopathies and highlights key areas where additional research is required.

Pediatric cardiomyopathies are rare diseases associated with poor outcomes. In such cases, left ventricular assist device implants and heart transplantation are therapeutic options, but they have limited applicability owing to several complications and donor shortage, respectively. Cardiac regeneration therapies are increasingly expected to solve this unmet medical need, and recent translational researches have already been implemented to improve cardiac function and to attenuate left ventricular remodeling in adult patients with myocardial damage. Various cells, including bone marrow, myoblast, and iPS cells, have been used in preclinical studies. This review presents recent advances in myocardial regeneration therapies and discusses cell transplantation therapy, myoblast cell-sheet therapy, human induced pluripotent stem cell-derived cardiomyocyte sheet therapy, and direct myocardial reprogramming therapy. Additionally, the importance of understanding fundamental developmental biology of cardiomyocytes becomes apparent.

In-situ cross-sectional morphology of the fetal and neonatal rat ductus arteriosus (DA) is studied by rapid whole-body freezing, cutting on a freezing microtome, and photographing the cross-section serially every 0.5 mm with a stereoscopic microscope (Wild M400). Thoracic sagittal sections reveal the right ventricular (RV) infundibulum, main pulmonary artery, DA, and descending aorta in one plane. This forms the major circulatory route in the fetus. Serial frontal and sagittal sections of the neonatal thorax reveal rapid tubular constriction at 1 hour and complete closure at 2 hours after birth. Fetal DA shows different patterns of pharmacological constriction. Fetal DA constriction by indomethacin is initially tubular at 1 and 2 hours after orogastric administration to the mother rat but becomes sandglass shaped and eventually becomes distal, short, tubular, or membranous at 8 and 24 hours after administration. These patterns of constriction are observed after pharmacological agents are administered transplacentally or directly to the fetus; this includes DA constriction after administration of cyclooxygenase inhibitors such as aspirin, indomethacin, and ibuprofen, constriction after administration of glucocorticoid hormones such as betamethasone, and constriction after administration of sulfonylureas such as glibenclamide and glimepiride. Persistent fetal DA constriction after administration of indomethacin for more than 24 hours induces RV concentric hypertrophy with diminished cavity and left ventricular dilatation with increased ventricular muscle mass in 4-chamber view sections.

Introduction: Chylothorax/abdomen can lead to prolonged hospitalization, cause developmental delays, and sometimes become fatal. Therefore, the development of a new therapy has been investigated. Owing to the rapidly expanding knowledge about central lymphatic disease, the etiology of chylothorax/abdomen has been found to be recurrent and to leak due to lymphatic stenosis or obstruction. These lymphatic problems are similar to those in peripheral lymphatic disease, for which we analyzed the lymphatic flow and treated it with direct maneuver. Based on this, we have introduced minimally invasive procedures to correct the central lymphatic system.

Material and Methods: We included 12 pediatric patients aged 30 days to 2 years. Five patients were diagnosed with hereditary diseases other than cardiac anomalies. All patients were followed for ＞6 months after the lymphatic procedures were performed. Medical treatment was preoperatively given for ≥4 weeks and with diet/milk restrictions.

Results: Four patients were completely cured from lymphatic leakage, three patients required further treatment, and five patients died during intensive care, mainly because of respiratory distress.

Conclusion: Lymphangiography and lymphatic venous anastomosis are the most commonly performed procedures that are effective in some patients. This novel treatment remains limited to patients with complications. However, the new therapy that is based on the lymphatic flow analysis may become a novel approach for refractory chylothorax/abdomen. Therefore, studies on lymphatic disease are ongoing and further improvements are expected in the future.

Background: This study aimed to ascertain midterm prognosis by comparing adult and child patients while accounting for the risk factors of complications and the effectiveness of the total cavopulmonary connection (TCPC) procedure.

Method: We analyzed data for 25 patients aged 18 or older who underwent TCPC procedure. The data for 75 patients aged 5 years or lower were analyzed for comparing the results.

Results: We observed perioperative complications in 13 patients including one perioperative death. The overall 5-year survival ratio after performing the TCPC procedure in adults was 96.0％, which was not different from that in child patients. On the contrary, cardiac events after discharge occurred more frequently in adult patients. Three patients died after performing the Fontan procedure in the observation period, all of whom had high end-diastolic pressure of the main ventricle and high pulmonary artery pressure. Cardiac events after discharge occurred more frequently among the patients with heterotaxy. Supraventricular tachyarrhythmia occurred more frequently after conducting the TCPC procedure in adult patients than in child patients both in the hospital and after discharge. Percutaneous oxygen saturation and cardiothoracic ratio improved significantly after the Fontan procedure; however, the mean cardiac index remained low at 1.9 L/min/m²．

Conclusion: The overall survival after performing the Fontan procedure with TCPC was satisfactory in adults. TCPC improved cyanosis and reduced volume overload in adult patients. However, certain patients may develop supraventricular tachyarrhythmia, and some may have high central venous pressure and low cardiac output after the surgery.

Providing safe management to enable women with inherited primary arrhythmia syndromes (IPAS) to have babies is very important, but no management policy has yet been established. To obtain clinical information about pregnancy in women with IPAS and provide an input on the development of a management policy, we retrospectively reviewed the clinical records of six pregnancies in three patients with catecholaminergic polymorphic ventricular tachycardia (one suspected case) and one pregnancy in one patient with long QT syndrome in our hospital from 2008 to 2016. We held multidisciplinary meetings with obstetricians, cardiologists, anesthesiologists, and neonatologists to develop a detailed plan. With the exception of one patient, we selected a planned cesarean section between 37 and 38 weeks of gestation; there were no cardiac events. In the pursuit of a secure management strategy, the accumulating of additional clinical information and cases of pregnancy in women with IPAS is needed.